Polyomaviruses are small non-enveloped double-stranded DNA viruses which display restricted species and cell-type specificity. Up to ten different polyomaviruses have been found in humans that have oncogenic potential and can cause chronic infections. JC virus, or John Cunningham virus (JCV), is a member of the Polyomaviridae family and the causative agent of Progressive Multifocal Leukoencephalopathy (PML), a life-threatening viral infection of the brain. BK virus (BKV) is also a human specific polyomavirus which is responsible for BK nephropathy and loss of graft in renal transplant patients. JCV and BKV are both opportunistic pathogens which infect the human population during early childhood, while the infection is mostly asymptotic. The seroprevalescence in adults is about 70-80% (Knowls, ADV. Exp. Med. Biol. 577 (2006), 19-45). The viruses remain latent mostly in the kidney cells of the host until reactivation which occurs in immunosuppressed individuals.
The viral capsid is about 40 nm in diameter and is formed by 72 pentamers of the VP1 protein. Each pentamer is associated with one molecule of either VP2 or VP3, the 2 minor capsid proteins. Only VP1 is exposed on the surface of the virus and it is therefore the protein responsible for the receptor binding. The virus genome is divided into early coding regions (small and large T antigens) and late coding regions (VP1, VP2, VP3 and agnoprotein).
Up to 90% of the global population has been exposed to JCV without developing any clinical syndrome. The virus can stay in a dormant state in patients for a long period of time and is kept under control by the immune system. However, JCV can be reactivated and can cause a demyelinating disease of the central nervous system (CNS), namely Progressive Multifocal Leukoencephalopathy (PML). PML is an opportunistic and often fatal infection that occurs in states of immunocompromise such as human immunodeficiency virus (HIV) infection, cancer, organ transplantation, haematological malignancies or rarely during autoimmune diseases. In Acquired immunodeficiency syndrome (AIDS) patients, PML was one of the most serious complications, although its incidence decreased after introduction of antiretroviral therapy.
Furthermore, immunomodulatory therapies that target immune cells or therapies for conditions such as Multiples Sclerosis (MS) as well as patients with liver or renal impairment, and patients with psoriasis, systemic lupus erythematosus, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, and Crohn's disease have an increased risk of incident of PML. JCV infects cerebelar granual cells, oligodendrocytes, astocytes, and pyramidal cells. So far its primary infection is restricted to kidney, epithelial cells, tonsillar stromal cells, bone marrow, oligodendrocytes, and astrocytes (Frenchy et al., Clin. Microbiol. Rev. 425 (2012), 471-506).
The pathogenesis of PML is characterized by a lytic infection of myelin-forming oligodendrocytes and abortive infection of astrocytes in the absence of a notable immune reaction. However, other central nervous system (CNS) cells such as cerebellar granule neurons can also be infected by JCV. The most frequent symptoms of PML include cognitive impairments, motor dysfunctions, visual deficits, seizures, impaired speech and headaches.
There is no specific antiviral drug against JCV to treat PML so the reconstitution or restoration of the immune system is the best solution. On the other hand, the increased immune system activity can lead to an important influx of lymphocytes into the brain and to the immune reconstitution inflammatory syndrome (IRIS).
Many broad-spectrum nucleotide analog chemotherapeutics that interrupt RNA and DNA synthesis including for example cytosine arabinoside, acyclovir, and cidofovir have been used to inhibit JC virus (JCV) replication in PML patients, but without much success (Frenchy et al., Clin. Microbiol. Rev. 25 (2012), 471-506).
In addition, further treatment strategies include inhibition of the virus entry into the host cell by for example 5HT2a antagonists, an increase in T cell amount by for example IL-2, plasma exchange in patients who develop PML as a consequence of for example natalizumab.
Identifying a therapy for the prevention of onset or treatment of PML addresses an urgent unmet medical need in several fields of medicine including acquired and hereditary immunodeficiencies, oncology, transplant medicine and autoimmune diseases. This often fatal viral disease represents a severe opportunistic infection associated with immunodeficiencies such as HIV infection, allotransplantation, and cancer chemotherapy. Over the past decades, the incidence of PML has significantly increased related to the AIDS pandemic and, more recently, to the growing use of immunosuppressive drugs. Reports of PML-related deaths of patients receiving natalizumab (Tysabri; Biogen/Elan) for Multiple Sclerosis (MS), efalizumab (Raptiva; Genentech/Merck Serono) for psoriasis, rituximab (Rituxan; Genentech/Biogen) for systemic lupus erythematosus, and infliximab (Remicade; Centocor) for rheumatoid arthritis and Morbus Crohn, highlight the tremendous negative impact of PML for the future use of these otherwise safe and efficacious life-saving treatments. After several cases of PML with fatal outcome efalizumab had to be withdrawn from the market. Similarly, recent estimates assume an incidence of PML in 1:500 MS patients, who are treated with natalizumab, with a strong increase beyond 2 years of treatment thus jeopardizing the further use of this currently most effective treatment for MS. Increased risk of PML is also evident for several novel drug candidates that are in late stage development for MS such as rituximab/ocrelizumab (anti-CD20; Roche) and alemtuzumab (anti-CD52; Sanofi-Aventis/Genzyme).
BK virus (BKV) is also widespread in the global population and the infection can stay asymptomatic. However, immune-compromised patients cannot repress anymore the viral replication and BKV reactivation can lead to several diseases. BKV became mainly an issue in cases of severe immune depression, for example in patients who received a transplant and who therefore had to take immunosuppressive drugs. In those patients, the virus can multiply inside the graft cells and cause a disease named BK nephropathy which can finally lead to graft loss. BKV is also an issue for patients who received a bone marrow transplant and who can develop a hemorrhagic cystitis. (Bogdanovic et al., Anticancer Res. 26 (2006), 1311-1318; Hirsch, Am. J. Transplant. 2 (2002), 25-30). However, in transplant recipients BKV reactivation is common and leads to distinctive pathological entries in different patient groups (Van Alderen et al., Neth. J. Med. 70 (2012), 172-183). Furthermore, the BKV can be reactivated in HIV infected patients leading to for example meningitis.
There is no available treatment to clear BKV infection. Some small molecules have been reported to limit the viral spread but their mechanisms of action are not entirely understood. The most efficient way to control the viral replication is to restore the immune system or to decrease the doses of immunosuppressive drugs. However, this could also lead to graft rejection.
Thus, there is a need for therapeutic means capable of preventing an infection or spreading of polyomavirus in the human body and the onset and progression of diseases related to polyomavirus infection including those, where common medical treatment activates polyomavirus replication such as the use of immunosuppressive drugs.
This technical problem has been solved by the embodiments characterized in the claims and described further below as illustrated in the Examples and Figures.